Microvascular obstruction detection and therapy

ABSTRACT

A method of detecting and treating a microvascular obstruction is provided. In one embodiment, a catheter is provided for both detecting the microvascular obstruction and treating or removing the obstruction.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/821,216 filed Aug. 2, 2006 entitled Microvascular ObstructionDetection And Therapy, U.S. Provisional Application Ser. No. 60/821,678filed Aug. 7, 2006 entitled Microvascular Obstruction Detection AndTherapy, U.S. Provisional Application Ser. No. 60/864,130 filed Nov. 2,2006 entitled Microvascular Obstruction Therapy III; and U.S.Provisional Application Ser. No. 60/864,336 filed Nov. 3, 2006 entitledMicrovascular Obstruction Therapy; all of which are hereby incorporatedby reference.

BACKGROUND OF THE INVENTION

Blockages of blood flow to the smaller blood vessels in the body, alsoreferred to as microvascular obstruction, often result in ischemicinsult and necrosis of nearby tissue. These microvessels circulate bloodto almost all major organs of the body, such as the heart, kidneys,skeletal muscles, and brain, as well as to more peripheral areas such asextremities, muscles and skin. In this respect, microvascular occlusionscan damage almost any area of the body, resulting in a wide range ofcomplications and diseases.

Generally, microvascular obstruction is caused by thrombotic occlusions(e.g., platelets, fibrin or both), vasospasm of the micro vessels (i.e.,sudden narrowing), leukocyte (white blood cell) or a combination ofthese. Due to the small size of the microvessels, typically 8-1500micrometers in diameter, detection of obstruction remains difficult.Further, even when obstruction is localized, effective treatments can besimilarly difficult to deliver.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a perspective view of a preferred embodiment of adetection and treatment catheter according to the present invention;

FIG. 2 illustrates a side view of a preferred embodiment of a detectionand treatment catheter according to the present invention;

FIG. 3 illustrates example pressure reading from pressure bleedsrelating to a microvascular obstruction;

FIG. 4A illustrates a conceptual diagram of pressure measurementsaccording to a preferred embodiment of the present invention;

FIG. 4B illustrates a pressure measurement system according to apreferred embodiment of the present invention;

FIG. 5 illustrates an example chart of resistance over time duringtreatment according to the present invention;

FIG. 6 illustrates a perspective view of another preferred embodiment ofa detection and treatment catheter according to the present invention;

FIG. 7 illustrates a perspective view of another preferred embodiment ofa detection and treatment catheter according to the present invention;

FIG. 8 illustrates a conceptual view of a detection and treatment systemaccording to the present invention;

FIG. 9 illustrates a side view of a dual balloon detection and treatmentsystem according to the present invention;

FIG. 10 illustrates a side view of the dual balloon detection andtreatment system of FIG. 9;

FIGS. 11A-11C illustrates various side views of a catheter tip accordingto a preferred embodiment of the present invention; and

FIG. 12 illustrates a graph of phasic flow according to a preferredembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Effective treatment of microvascular obstruction ideally focuses oninitially detecting the presence and specific location of anobstruction, then treating the location to remove or at least reduce theblockage. While different preferred embodiments of detection andtreatment methods are discussed below, it should be understood thatthese techniques can be used alone, in combination with each other or incombination with other techniques not specifically disclosed in thisspecification.

Detection of Microvascular Obstruction

In one preferred embodiment, microvascular obstruction is detected withMRI imaging. The patient is imaged in the general location where theobstruction is thought to be. The doctor then reviews these MagneticResonance Imaging (MRI) Images to locate the precise position of theobstruction. Once located, the obstruction can be removed by any of theremoval techniques discussed in this specification.

In one preferred embodiment, microvascular obstruction is detected bymonitoring a loss or diminution of blood flow or perfusion in a focalpiece of a muscle or tissue. For example, blood flow can be monitored byproducing a 1 MHz ultrasonic signal from an offsite catheter or from anultrasonic signal from a treatment catheter. Reflections of the signalare utilized to detect microvascular extraction and additionally toenhance dissolving the obstruction as discussed in further detail below.

In another preferred embodiment, microvascular obstruction is detectedby measuring a wedge pressure (wedge pressure being generally defined asthe intravascular pressure reading obtained when a fine catheter isadvanced until it completely occludes a blood vessel, or with a smallballoon used to occlude the vessel distally. For example, wedge pressurewithin the myocardium may be detected with a catheter having two or morepressure measuring balloons (e.g., low pressure balloons). As themyocardium contracts, it squeezes the microvasculature and likelyincreases the external pressure on the vessels. As this pressureincrease occurs, the nearby vessels may close during systole, allowingpressure in the proximal coronary artery to be sensed over time. If theproximal vessel is partially or completely occluded by, for example, aballoon, the pressure in the vessel distal to the balloon and proximalto the myocardium will be sensed as a rhythmic rise in proportion tomyocardial contraction.

When a microvascular obstruction is present, the pressure waveform isdamped in amplitude, frequency, or even completely absent, depending onwhether a vessel is completely or partially occluded. This pressurewaveform of an occluded vessel is comparatively different from normalunoccluded microvasculature, for example, by comparing the amplitude,frequency and flow. However, the condition of the myocardial contractionwill also affect this pressure waveform. As the “squeeze” damps thewaveform to zero (i.e., the muscle is not contracting) the pressurewaveform will be substantially damped as well. As the occlusion isimproved in the micro vessel, and/or as the myocardial contractionoccurs more vigorously, the waveform may, for example, increase inamplitude in a proportional manner. In this respect, the pressuremeasurement provides information over time regarding the success andprogress of the microvascular treatment.

In this respect, amplitude, frequency and flow all find use to guide thetherapy (e.g., delivery of treatment agents) of a microvascularobstruction. As the obstruction is improved and as the myocardialcontraction occurs more vigorously, the pressure waveform will increasein amplitude in a proportional manner. Measuring the waveform's changesover time during treatment will yield useful information regarding thesuccess and progress of the treatment. Further, a catheter may be placedin the myocardial venous system and a time-varying pressure waveformintroduced to measure from the arterial side, also for determination ofthe microvasculature in a similar manner as above using the naturalwaveform generated as the heart muscle contracts.

In another preferred embodiment, microvascular obstruction is detectedby measuring vascular impedance within a patient. Vascular impedance isgenerally defined as blood pressure divided by the blood flow andtherefore is obtained by measuring blood pressure and blood flow (e.g.,velocity or volumetric) within a vessel. Preferably, these readings aremeasured by inflating a balloon of a catheter within a vessel, thenmeasuring relevant data such as pressure, flow, and volume or flowcaused by the dispensed treatment agents while the balloon causesobstruction of the vessel. As multiple readings are taken from differentlocations within the vessel, the resulting data can be analyzed to helpdetermine the location of the microvascular obstruction. This readingmay occur in ‘real time’ as the fluid, which may contain therapeuticagent or agents, is injected into regions of microvascular obstruction.

The nature of a microvascular obstruction is such that it augmentsphasic resistance 122, seen in FIG. 12, and hence measuring phasicpressure amplitude, direction, and phase timing can indicate both theinitial severity of the microvascular obstruction and the response tothe therapy. More specifically, the microvascular thrombus or otheroccluding matter fill is incomplete during an obstruction and thereforephasic squeezing of the coronary microvessels by myocardial contractioncreates a phasic antegrade pressure that can be measured. In cases ofsevere microvascular occlusion, contrast exhibits phasic flow and may bepumped in a retrograde direction during myocardial systole since thisretrograde flow is blocked by the obstruction.

With myocardial contraction, it is likely that the resistance parameter(pressure/flow, or by dimensions, mmHg/ml-min) is a useful absolute andrelative marker of MVO and proportional in severity. Infusion of fluidat a constant flow rate can cause phasic variation in distal catheterpressure during myocardial systole. The pressure can be measured in theflow scenario and an estimated of MVO severity obtained. This distalresistance creates an accurate, real-time method to measure suchresistance. Further, this resistance is phasic and the parameters of thephasicity can determine the severity of the MVO.

The mean 120 (also in FIG. 12) of the phasicity or other derivedwaveform from the phasicity may also be processed for determiningalternative parameters of the MVO severity. This concept uses anon-constant, varying parameter to measure or process and derive aphysiological number related to an MVO parameter.

Treatment of Microvascular Obstruction

In one preferred embodiment according to the present invention,treatment of a microvascular obstruction is achieved by dissolving theemboli by delivering one or more treatment agents to the obstruction(e.g., with a balloon treatment catheter described elsewhere in thisspecification). This combination of fluids may be simultaneous as in amixture, or as separate injections. Since these obstructions or emboliare typically composed of platelet/fibrin emboli, dissolution iseffectively achieved, in one example, by a multifactorial approach thatincludes inhibition of the intrinsic, extrinsic and platelet“disaggregation”. In a more specific example, a combination ofglycoprotein IIB/IIIA inhibition, direct thrombin inhibition, indirectthrombin inhibition, and a clotting factor such as Factor X, Factor VII,or other factors in this clotting pathway can be used. In another morespecific example, a combination of argatroban, any IIB/IIIA agent, TickAnticoagulant Peptide, echistatin, Integrilin, PPACK, and DPG peptideinhibitor can be delivered to an occlusion.

Additionally, a traditional fibrinolytic agent such as TNK,streptokinase, urokinase, or rTPA may also be included, as well asantispasmotic agents such as adenosine, nitroglycerin, sodiumnitroprusside, nicorandil or similar agents capable of relieving microor macrovascular spasm. Further examples of treatment agents includeHirulog, Bivalrudin, ReoPro, eptifibatide, TAP, Heparins, LMW Heparins,Argatroban, Hirudin, Refludan/Lepirudin (Berlex), Desirudin, Recombinantforms, ABCIXIMAB, Eptifibatide, Tirofiban, Alteplase, Reteplase,Tenecteplase, Factor Xz, rivaroxaban, and Fodaparinux.

Additional treatment agents may include agents active againstaccumulation of polymorphonuclear leukocytes. Inhibition of these cellswill be myocardial protective. Specific examples may includeanti-inflammatory agents, adenosine, anti-PMN antibodies, anti-leukocyteantibodies, quinolone agents, nitrogen mustard, and hydroxyurea. Furthertreatment agents may include anti-serotonin agents, such as cinanserin,pizotifen, cyproheptadine, lysenyl, mianserin, methysergide,promethazine, octreotide, and others.

In another example, intermediate and older clots are treated withenzymes known to be more effective in treating these types ofobstruction, such as trypsin, papain, chymotrypsin and similarproteolytic agents. These agents are preferably infused under pressureat a microvascular obstruction to drive the agents into the obstructionto enhance efficacy against the obstruction.

More specifically, the treatment agents can be delivered locally intothe microvasculature via catheter placed into the larger surroundingvessels, then diffusing these agents, either alone or under pressurewith balloon occlusion. Alternately, these agents may be injectedretrograde to the coronary venous system where the obstruction can bedissolved. Often, the obstruction is quite porous and will acceptdiffusion of a treatment agent or series of agents when dissolved in asolution such as water or saline.

This infusion pressure is preferably gated with the ECG waveform,providing the highest pressure as the heart is relaxing and the lowestwhen the heart is contracting, thereby infusing the micro vessels attheir most receptive time in the cardiac cycle. Alternately, thepressure function/waveform may be other than a constant pressure and maybe periodic, possibly though not necessarily gated to the cardiac cycle.For example, the function/waveform may be a pulse, square wave,sinusoidal, or other non-constant pressure waveform. The contour of thewaveform at the tip of the treatment catheter is a function of theperipheral resistance and serves as a diagnostic technique.

The treatment agents may further include anti-arrhythmic agents toprevent or limit reperfusion arrhythmias. For example, class I, II, andIII anti-arrhythmia agents can be used, as well as lidocaine, quinidine,amiodarone, procainamide, propofenone, and beta blockade.

The treatment agents delivered to the microvascular obstruction mayfurther include agents to restore microvascular integrity and limitcapillary leakage. Preferably, these agents may act to limit capillaryaccess by coating the surface of the microvascular lumen. For example, aprotein or other weight carbohydrate infusion including albumin or LMWDextran can be used. These agents may be oxygenated to enable moreprolonged infusion. Further, antibody coatings may also be included toprevent cellular demargination, such as CD 18 (anti-), or to attracthealthy cells such as CD 133 or CD 34 positive cells.

The treatment agents may further include agents that are known to thoseskilled in the art to produce electrical or mechanical arrest of tissuesurrounding the microvascular obstruction to prevent damage due to poorblood flow. Generally, use of such agents will temporarily halt orsignificantly limit metabolic activity to prevent arrhythmias and limitenergy consumption and therefore energy needs for the infracted region.Preferably, application of these agents are delivered to the tissue areadownstream of the microvascular obstruction, placing this tissue in atemporary “sleep” until the obstruction can be cleared and normal bloodflow returned to the tissue area.

Lysis of the obstruction is optionally detected or further confirmed byan inline sensor on a delivery catheter that detects small particulatematter. Preferably, this emboli sensor provides real-time lytic activitywhich allows a user to collect lytic material and/or treatment drugs atan appropriate time (i.e., as the emboli is dissolving) to prevent theirrelease into the patients circulatory system. For example, a cathetermay include a sensor that detects light refraction, reflection ortransmission. In this example, particles scatter light in a specificfashion and therefore indicate that lysis has occurred. Once the sensorhas detected that lysis has occurred, the user can quickly remove (e.g.,suction out) any of the embolic particles and treatment agents toprevent unintentional damage to other areas of the circulatory system.

Alternately, the pressure at the distal end of the catheter can besimilarly monitored so that when a drop in pressure is detected (i.e.,the obstruction is broken up or dissolved) the user can immediately stopinjecting treatment agents to the vessel and suction out any remainingdebris or treatment agents.

While the liquid containing the thrombotic components and treatmentagents can be permanently removed from the patient, this liquid canalternately be returned to circulation after filtration of the unwantedmaterials (such as chemicals and proteins), returning only the desiredportions of the liquid (e.g., red blood cells, white blood cells andplatelets). For example, the liquid can be filtered through a porousfilter membrane by centrifugal or mechanical force which allows thesmaller protein and chemical particles to pass through while holding thelarger blood cells.

In another preferred embodiment, the microvessels are constricted(including those that are patent), with vasoconstricting agents forexample (e.g., norepinephrine, epinephrine, dopamine, phenylenphrine,alpha agonists, and caffeine), prior to treatment of the obstruction.These constricting agents constrict the vessels distal of themicrovascular bed so that the later applied treatment agents (e.g., clotlysis agents and anti spasmodic agents) are not washed out through thepatent microvessels. Thus, the treatment agents may be held in place fora longer period of time. In many cases of MVO, it is suspected that aportion of the microvessels are patent and others are not patent, due toboth spasm and thrombosis.

In a similar preferred embodiment, a proximal balloon with negative andpositive pressure cycling (as described elsewhere in this specification)can be used to achieve constriction. Microvessels are collapsed undernegative pressure and proximal blood is aspirated and replaced duringthe positive pressure cycle, along with treatment agents including ananti-spasmodic agent and a platelet/thrombus lysing agent.

In another preferred embodiment according to the present invention, theeffects of the lytic agents can be augmented by exposure of anultrasonic field. For example, ultrasonic energy in the frequency rangeof about 0.5 MHz-10 MHz is produced near a microvascular obstruction,either externally through the skin's surface or internally from a nearbylarger vessel. In this respect, the ultrasonic energy radiates to theobstruction, increasing the rate of dissolution of the obstruction bythe treatment agents alone.

In another preferred embodiment according to the present inventionmicrovascular obstruction therapy of thrombus dissolution can beassisted by first isolating a vessel enabling pressure to varyindependently (barometric isolation), and then cycling the pressurepositive and negative at an arbitrary frequency. During the cycling, alytic solution for the thrombus is introduced, and is driven into theoccluding microvessel-thrombus during the positive pressure cycle. Inaddition, the negative pressure cycle has the tendency to withdraw thethrombus from its micro-vessel. The positive and negative cyclingrequires a segment of artery to be isolated. This is accomplished by adouble balloon technique, or alternatively by a system that blocksproximal and distal flow to the desired region of the vessel.

This technique includes the cessation of antegrade flow, accomplished bya proximal obstructing system, typically balloon that is inflated. Theentire system, through its cycling facilitates uptake by the attractingmicrovessel of a drug or drug combination that is specifically directedtoward relieving spasm in the vessel, dissolving the clot, and expandingthe vessel around the clock to permit its extraction through thenegative pressure cycle.

The use of pressure cycling techniques may include a physical structurethat is temporarily placed into an artery while it is being treated.This structure may prevent the vessel from collapsing duringimplementation of lower than ambient pressure. Preferably, such a devicemay be a catheter with a mechanical support structure. It may havestructural components that are straight, spiral, helical or any otherconfiguration that permits vascular support. It may be self expanding ormaybe expendable by a balloon. It may further be a balloon, filled withfluid and capable of supporting the vessel as negative pressures placedon that vessel.

In another preferred embodiment according to the present invention, agas that is typically quite soluble in blood or water is infused into avessel to permit access by that vessel of a potent drug. The gas mayconsist of nitric oxide carbon dioxide or other highly soluble gas. Asthe gas is infused into the vessel, specifically up to and includingregions of thrombus. The bubble may be a carrier for, for example, lyticor anti-spasmodic agents. The bubble concept through utilization of suchgases may also clear blood from the field and allow approach of a liquidform of the drug, up to and including the microvasculature.

Myocardial protection during anti-spasmodic therapy and plateletlysis/clot lysis therapy may be followed by a procedure utilizing anagent that is designed to protect heart muscle. The substance mayinclude a cool liquid, at any temperature less than body temperature andcan be supplied during or after the treatment procedure. It may alsoentail, as discussed elsewhere in this specification, agents that causea rest of the myocardium.

Catheter for Removing Microvascular Obstruction

Referring to FIGS. 1 and 2, a single detection and treatment catheter100 is illustrated according to a preferred embodiment of the presentinvention. The catheter 100 includes a pressure transducer for detectinga microvascular obstruction, diffusion holes 104 for releasing treatmentagents near an obstruction and an occlusion balloon 106 for preventingthe treatment agents from moving through the patient's circulatorysystem. In this respect, the catheter 100 can both detect and treat anobstruction with a single catheter.

More specifically, the catheter 100 senses the location of amicrovascular obstruction (e.g., with pressure readings, ultrasound dataor other sensor readings). When the obstruction has been located and thedistal end of the catheter 100 positioned near the obstruction, theballoon 106 is expanded, creating a sealed area between the obstructionand the balloon 106. Next, the user releases treatment agents throughthe diffusion holes 104 into the sealed area to begin dissolving theobstruction. The user can continue to monitor the sensor readings (e.g.,pressure) to monitor the progress of the obstruction's dissolution.During this process or prior to dissolution of the obstruction, thecatheter circulates the fluid within the sealed vascular area andfilters out obstruction material (e.g., proteins) and treatment agents,preventing these materials from freely circulating in the patient'svascular system.

Preferably, the catheter 100 includes a guide wire lumen for placementwithin a patient and may be configured for “single operator exchange”.

As previously described, pressure measurement can be used to determinethe location of the obstruction and whether the treatment has dissolvedor broken up the obstruction.

In one example, a pressure measurement transducer is integrallyconnected to the agent delivery lumen at either a proximal or distal endof the catheter 100. The pressure may be measured directly to establishthe myocardial resistance (pressure divided by flow). In a secondexample, a distal hole 102 as seen in FIG. 1 opens to a hydraulic columnwhich is further connected to a pressure transducer. In this respect,the catheter 100 includes at least two lumens, one for delivery of thetreatment agents and another for the pressure transducer. In a thirdexample, a micromanometer sensor may be disposed at the distal tip ofthe catheter to obtain a pressure reading.

In a fourth example, pressure is sensed at the distal tip of thecatheter by including two or more low pressure balloons that measure themyocardial squeeze that occurs in the myocardium. As the myocardiumcontracts, it squeezes the microvasculature and typically increases theexternal pressure on the vessels. As this occurs, the vessels oftenclose during systole in some or even all vessels which allows thepressure in the proximal coronary artery to be sensed over time. If thevessel proximal to the catheter 100 is partially or completely occludedby, for example, a balloon, the pressure in the vessel distal to theballoon and proximal to the myocardium will be sensed as a rhythmic risein proportion to the myocardial contraction.

If microvascular obstruction is present, this pressure waveform isdamped or absent completely, depending on whether the obstruction iscomplete or not. In this respect there is a comparatively differentpressure waveform that is different than when measuring a normal,unobstructed microvasculature. This myocardial contraction will alsoaffect the pressure waveform, dampening it as the “squeeze” reduces asthe contracting muscles relax. Similarly, the catheter 100 may be placedin the myocardial venous system and a time-varying pressure waveformintroduced to measure pressure from the arterial side. Similarly, thenatural waveform generated as the heart muscle contracts can be used ina similar manner as previously described to monitor the obstruction.

The pressure measurements or similar sensor data (e.g., resistance) maybe further communicated to the injector system as feedback data. In thisrespect, the injector system can regulate the treatment agents based ona pressure reading. For example, if the injector system receivespressure readings that are declining, it may reduce the amount oftreatment agents being delivered. In another example, the injectorsystem may receive a dramatic drop in pressure readings indicating theobstruction has been dissolved and therefore stops the injection of thetreatment agents.

In addition to pressure, flow sensors and flow sensor technology may beused to monitor the injection rate of treatment agents. In one example,flow sensing is performed by monitoring injection rates by tracking amenu displacement transducer that corresponds to a hydraulic driver forfluid (i.e., the treatment agents).

As previously discussed, the occlusion balloon 106 seen in FIGS. 1 and 2is inflated within a patient's vessel, creating a sealed area thatprevents treatment agents from freely moving into the circulatory systemand facilitating pressure monitoring. Preferably, the occlusion ballooncomprises a soft, compliant material that can be inflated to lowpressures to prevent blood flow from entering the vessel.

As seen best in FIG. 1, the diffusion holes 104 are a plurality of smallholes in communication with a lumen with in the catheter 100. Theseholes 104 diffuse the liquid (e.g., treatment agents) that may otherwisecreate a single jet. These single jets can cause damage to the vesselwall at high flow rates. Preferably, the diffusion holes 104 have agradient in size or number in proportion to length (e.g., hole sizeincreases in the distal direction) to allow equal drug efflux from allof the holes 104. Similar holes are described in more detail in U.S.Pat. No. 6,949,087, the contents of which are hereby incorporated byreference.

As seen in FIG. 6, the catheter 100 may have multiple diffusion holeareas 104A-104C to more diffusely release the treatment agents.Similarly, FIG. 7 illustrates a catheter 100 with a single, elongateddiffusion hole region 104D.

FIGS. 11A-11B illustrate a distal catheter end 103 for the catheter 100having a virtual distal port which allows the guidewire 105 to passthrough, but prevents leakage around the guidewire 105. Instead of anaperture or port, the material of the catheter end 103 grabs theguidewire 105 to create a tight seal. FIG. 11C illustrates a distalcatheter end 103 with a virtual distal port and a plurality of diffusionports 107 for diffusing a treatment agent.

Referring to FIGS. 9 and 10, a double balloon catheter 120 isillustrated which permits distribution of a treatment agent into a shortsegment of vessel (e.g., artery). This catheter 120 may be particularlyuseful in the coronary arteries where a branch or branches within agiven localized region of heart muscle requires a therapeuticintervention to dispense a treatment agent.

As seen in FIG. 10, the catheter 120 is positioned near a target vessel132 and within an adjacent vessel 130. Both balloons 106 are inflated,blocking circulation within the adjacent vessel 130 and therefore withinthe target vessel 132. Once sealed from the greater circulatory system,the diffusion holes 104 release the treatment agent into the targetvessel 132 while a pressure port 110 allows the pressure and thereforethe obstruction removal progress to be monitored.

The balloons 106 may be connected to the same inflation lumen andtherefore inflated simultaneously or can be connected to differentinflation lumens to allow for individual inflation. The distance betweenthe two balloons 106 is preferably between 2 mm and 5 cm, but may bemore or less depending on the size of the target vessel 132 and theshape of the adjacent vessel 130. As with previously discussedembodiments within this specification, the pressure port 110 connects toa proximal portion of the catheter for sensing pressure. Alternately, atransducer may be positioned within the catheter 120, between the twoballoons 106. As with previously discussed embodiments in thisspecification, additional diagnostic sensors and catheters may be usedto determine microvascular integrity, where increased hydraulicresistance indicates significant microvascular obstruction.

Referring to FIG. 8, the detection and delivery system preferablyincludes an injector 150, a hydraulic reducer 152, a flow sensor 154, anagent chamber 156, a bubble chamber 158, and a pressure sensor 160.

Turning first to the injector 150, this unit drives the injection of thetreatment agents. Preferably, the injector is configured to deliver thetreatment agents at a constant flow rate which facilitates the accuratemeasurement of pressure within the system. Such pressure measurementprovides a direct analog of distal myocardial or organresistance/impedance. For example, this resistance/impedance isanalogous to two electrical impedances in series. More specifically andas seen in FIG. 4A, a constant flow source provides for a pressure beingmonitored at a junction point between two impedances. This monitoredpressure is directly analogous to the magnitude of the second serialimpedance. This resistance (e.g., myocardial resistance) equals thepressure divided by flow, and so can be determined at any point bymeasuring the pressure when the flow is constant. However, in somesituations the flow will not be constant, such as when feedback data iscommunicated to the injector, and so both pressure and flow must bemeasured. As seen in FIG. 5, the resistance will drop as the treatmentagents remove the obstruction.

In an alternate example, FIG. 4B illustrates a catheter 100 with aplugged distal port for measuring microvascular resistance. A flow pump130 provides a constant flow source to the catheter 100 near themicrovasculature 140 and pressure measurements are taken at a location136 proximal to a fixed resistance 132 and a location 138 distal to thefixed resistance 132. Distal flow is calculated from the pressuredifferential across the proximal resistance 132 and the known, fixedinfusion rate. Pressure at the catheter infusion tip is a surrogate formicrovascular resistance and is measurable in real time.

Turning next to the hydraulic reducer 152, this unit enables driving thesystem from a drug and/or contrast standpoint with a proximal inletport. The hydraulic reducer comprises a linear ram of differentdiameters, such that comparable linear displacement yields a fixedvolume reduction in proportion to the relative areas of the hydraulicram. Further details of hydraulic reducer technology can be seen in U.S.Patent Publication Number 2005-0165354, the contents of which are herebyincorporated by reference.

Turning next to the agent chamber 156, this unit contains anddistributes the treatment agents that are pushed through a bubbledetection chamber 158, past a pressure transducer 160 (for measuringpressure of the fluid), and through the catheter 100 and into the vesselof the patient.

Preferably, real time impedance readings are calculated during aprocedure which allows a user to monitor the removal progress of theobstruction. Thus, as treatment is infused from the catheter diffusionholes 104, the effect of the treatment can be immediately observed by amyocardial impedance drop (e.g., a pressure drop if flow remainsconstant since impedance is pressure divided by flow).

Since the treatment agent is delivered in a fluid form through thediffusion holes 104, the treatment agent and its delivery passages canbe used to monitor both the flow and pressure readings needed tocalculate impedance, as seen in FIG. 8. Additionally, the impedance ofthe system may be increased to produce more sensitive detection of theobstruction. For example, higher impedance may be achieved by includingsmaller inlet ports at locations prior to the catheter 100 or a smallbladder lumen in the catheter itself which becomes integral in providinga constant flow source and may be further augmented by including a smalldiameter port that feeds fluid into the system. Measuring absolutevolume injected and the rate of that line of injection via methods suchas time differentiation/time derivative will give an accurate estimationof flow. Utilization of the flow parameter in conjunction with pressurewill calculate myocardial impedance or distal organ impedance.

Alternately, the presence and degree of the obstruction can becalculated by creating a pressure head at the origin of the vessel andmeasuring the “bleed off” of pressure, as seen in FIG. 3. This can leadto a first or second order exponential decrease in standard parameterssuch as “Tau” which can be calculated so as to directly determine thepresence and degree of vessel obstruction. Tau is an exponentialconstant commonly used in a decreasing parameter system.

In another preferred embodiment, a second simultaneous pressure readingtaken at a location proximal to the main distal pressure reading (e.g.,from a port proximal to the diffusion holes 104) can be obtained,allowing the two pressures to be compared. The second pressure readingcan provide a strong analog to the distal impedance and therefore betteridentify and quantify the obstruction. Similarly, the system may includemultiple pressure sensors (e.g., transducers) on the same fluid line toobtain a more accurate pressure reading.

As previously discussed, the delivery catheter may produce ultrasoundenergy in addition to treatment agents to more quickly dissolve anobstruction. For example, catheters produced by the EKOS Corporationsuch as the EKOS Lysus Peripheral Infusion System can be used for thispurpose and further modified to include additional features described inthis specification, such as pressure and flow sensing. The ultrasoundenergy is thought to make fibrin more accessible to the treatment agentswhile driving the treatment agents into the obstruction. Further, theultrasound energy may allow the treatment agents to be delivered throughtissue layers within the patient such as the adventitia.

The delivery catheter may also produce ultrasound energy for imaging anddetection (e.g., using a Doppler analysis) as previously described inthis specification.

One preferred embodiment of the present invention includes treating amicrovascular obstruction comprising locating a position of saidmicrovascular obstruction within a vasculature of a patient; advancing adistal end of a treatment catheter through said vasculature and withinproximity of said position of said microvascular obstruction; expandingan occlusion member within said vasculature; delivering a treatmentagent between said expanding occlusion member and said microvascularobstruction; and monitoring treatment of said microvascular obstruction.

Alternately in this preferred embodiment, said locating a position ofsaid microvascular obstruction within a vasculature of a patient isselected from a group of: magnetic resonance imaging, ultrasoundimaging, pressure measurement, vascular impedance measurement and phasicflow measurement.

Alternately in this preferred embodiment, said expanding an occlusionmember within said vasculature further comprises expanding a secondocclusion member within said vasculature.

Alternately in this preferred embodiment, said expanding an occlusionmember within said vasculature further comprises inflating an occlusionballoon.

Alternately in this preferred embodiment, said delivering a treatmentagent between said expanding occlusion member and said microvascularobstruction further comprises delivering one or more treatment agentsselected from the following group: Factor X, Factor VII, a IIB/IIIAagent, Tick Anticoagulant Peptide, echistatin, Integrilin, PPACK, DPGpeptide inhibitor, TNK, streptokinase, urokinase, rTPA, adenosine,nitroglycerin, sodium nitroprusside, nicorandil, Hirulog, Bivalrudin,ReoPro, eptifibatide, TAP, Heparins, LMW Heparins, Argatroban, Hirudin,Refludan/Lepirudin (Berlex), Desirudin, recombinant forms, ABCIXIMAB,Eptifibatide, Tirofiban, Alteplase, Reteplase, Tenecteplase, Factor Xz,rivaroxaban, Fodaparinux, adenosine, anti-PMN antibodies, anti-leukocyteantibodies, quinolone agents, nitrogen mustard, hydroxyurea,anti-serotonin agents, such as cinanserin, pizotifen, cyproheptadine,lysenyl, mianserin, methysergide, promethazine, octreotide, trypsin,papain, chymotrypsin, lidocaine, quinidine, amiodarone, procainamide,propofenone, and beta blockade.

Alternately in this preferred embodiment, said delivering a treatmentagent between said expanding occlusion member and said microvascularobstruction further comprises disbursing said treatment agent throughdiffusion apertures of said catheter.

Alternately in this preferred embodiment, said disbursing said treatmentagent through diffusion apertures of said catheter further comprisesdisbursing said treatment agent through a diffusion aperture region havea size gradient of said diffusion apertures.

Alternately in this preferred embodiment, wherein said monitoringtreatment of said microvascular obstruction further comprises measuringmyocardial resistance.

Alternately in this preferred embodiment, wherein said measuringmyocardial resistance further comprises measuring flow and pressure of afluid supplied between said expanding occlusion member and saidmicrovascular obstruction.

Another preferred embodiment of the present invention includes a methodfor treating an obstruction of a microvascular vessel within a patient,comprising advancing a distal end of a guidewire to a location incommunication with said obstruction; advancing a distal end of saidtreatment catheter over said guidewire to said location in communicationwith said obstruction; releasing a treatment agent from said treatmentcatheter; monitoring an impedance of said microvascular vessel; stoppingsaid releasing of said treatment agent when said impedance indicatesremoval of said obstruction.

Alternately in this preferred embodiment, said monitoring an impedanceof said microvascular vessel comprises determining an impedance bydividing a flow measurement of said treatment agent by a pressuremeasurement of a location in communication with said microvascularvessel.

Alternately in this preferred embodiment, said flow measurementcomprises measuring a pressure differential between a fixed resistancein communication with said microvascular vessel.

Alternately in this preferred embodiment, said pressure measurement of alocation in communication with said microvascular vessel is measuredwith a pressure transducer coupled to said treatment catheter.

Alternately in this preferred embodiment, further comprising exposingsaid obstruction to ultrasonic energy.

Another preferred embodiment of the present invention includes a systemfor treating a microvascular obstruction comprising: a treatmentcatheter comprising: an expandable occlusion balloon disposed on adistal end of said treatment catheter; a first lumen; a plurality ofdiffusion holes in communication with said first lumen and located atsaid distal end of said treatment catheter; and a selectively expandableocclusion member disposed at said distal end of said treatment catheter;an injector in communication with said first lumen for delivering atreatment agent through said catheter; and, an occlusion sensor formonitoring a level of blockage by said occlusion.

Alternately in this preferred embodiment, said treatment catheterfurther comprises a second selectively expandable occlusion member.

Alternately in this preferred embodiment, said occlusion sensorcomprises a pressure port at said distal end of said treatment catheter.

Alternately in this preferred embodiment, said occlusion sensorcomprises a pressure transducer at said distal end of said treatmentcatheter.

Alternately in this preferred embodiment, said occlusion sensorcomprises a flow sensor coupled to said first lumen.

Alternately in this preferred embodiment, said flow sensor comprises afirst pressure sensor and a second pressure sensor in communication withsaid first lumen for measuring a pressure differential of a resistancemember having a fixed resistance.

Although the invention has been described in terms of particularembodiments and applications, one of ordinary skill in the art, in lightof this teaching, can generate additional embodiments and modificationswithout departing from the spirit of or exceeding the scope of theclaimed invention. Accordingly, it is to be understood that the drawingsand descriptions herein are proffered by way of example to facilitatecomprehension of the invention and should not be construed to limit thescope thereof.

1.-20. (canceled)
 21. A system for treating a thrombotic or spasmodicobstruction of a vessel with a treatment agent, the system comprising:a. an injector configured to deliver the treatment agent; b. a treatmentcatheter fluidly coupled to the injector, wherein said treatmentcatheter comprises: i. two vessel occlusion members, wherein each of thetwo vessel occlusion members are located on a distal portion of thetreatment catheter and are separated so as to span an adjoining,adjacent vessel during a treatment; ii. a plurality of diffusion holesdisposed between the two occlusion members and configured to release thetreatment agent to the vessel site spanned by the two occlusion members,during treatment; iii. at least two lumens, wherein a first lumen of theat least two lumens is coupled to the two vessel occlusion members toallow for inflation of the two vessel occlusion members, and wherein asecond lumen of the at least two lumens is fluidly coupled from theinjector to the plurality of diffusion holes and configured to deliverthe treatment agent from the injector, through the diffusion holes, andto the vessel; iv. a pressure monitoring element disposed between thetwo occlusion members and communicatively coupling the treatmentcatheter to the vessel.
 22. The system of claim 21, wherein the firstlumen of the at least two lumens comprises a first vessel occlusionlumen and a second vessel occlusion lumen, wherein the first vesselocclusion lumen is configured for inflation of a first of the two vesselocclusion members, and wherein the second vessel occlusion lumen isconfigured for inflation of a second of the two vessel occlusionmembers.
 23. The system of claim 21, wherein the at least two lumenscomprise a third lumen fluidly coupled to the pressure port.
 24. Thesystem of claim 21, wherein a distance spanned by the two vesselocclusion members is between 2 mm and 5 cm.
 25. The system of claim 21,wherein the pressure monitoring element further comprises a pressureport fluidly coupled to a pressure transducer.
 26. The system of claim21, wherein the pressure monitoring element comprises a pressuretransducer.
 27. The system of claim 21, wherein the treatment catheterfurther comprises a guide wire lumen extending at least partially alonga length of the treatment catheter and configured to receive a guidewire.
 28. The system of claim 28, wherein the guide wire lumen isconfigured for single operator exchange use.